Atypical Lipomatous Tumor

Atypical Lipomatous Tumor /
Well-Differentiated Liposarcoma

Atypical lipomatous tumor and well-differentiated liposarcoma are both locally aggressive, low-grade malignant tumors that arise from adipose tissue. They feature adipocytes that are variably sized and irregularly shaped, as well as fibrous bands or septa that divide the tumor into lobules.

Although atypical lipomatous tumor and well-differentiated liposarcoma are morphologically similar, two distinct names are used to highlight key differences between them: the typical location and the risk for metastasis. Atypical lipomatous tumors are those lesions in this class that are found in the extremities, whereas Well-differentiated liposarcomas are found in the retroperitoneum, mediastinum, or spermatic cord. Also, atypical lipomatous tumors have no risk of metastasis (and are therefore not labeled as a sarcoma). Well-differentiated liposarcomas can metastasize, although the risk of metastasis is relatively low.

Epidemiology

Atypical lipomatous tumor and well-differentiated liposarcoma are common in older adults, with a peak incidence in the sixth and seventh decades of life. These patients tend to be older than those with lipomas. The tumors most typically involve the deep soft tissues of the thigh, but can also arise less commonly in the subcutaneous tissues of the extremities. The overall incidence of atypical lipomatous tumor and well-differentiated liposarcoma is about 1 in 200,000 people per year.

Several risk factors have been associated with the development of atypical lipomatous tumors and well-differentiated liposarcomas, including prior radiation exposure and certain genetic conditions such as hereditary retinoblastoma and Li-Fraumeni syndrome. However, in most cases, these tumors arise spontaneously without any known risk factors.

Clinical Features

An atypical lipomatous tumor typically presents as a slow-growing, painless mass in the deep soft tissues of the extremities. The mass can enlarge over the course of several years.

On physical exam, atypical lipomatous tumors are large, soft, compressible masses without nodularity. This stands in contrast to higher-grade sarcomas, which tend to be firm. Generally, the mass will be mobile on physical exam.

Well-differentiated liposarcoma in the retroperitoneum often presents late, as there may be no symptoms when the tumor is small and does not compress or obstruct vital structures. Because of this late presentation and their presence within the complex anatomy of the abdomen, patients with these tumors follow a more morbid clinical course.

Radiologic Features

Magnetic resonance imaging (MRI) with and without contrast is the best imaging modality to evaluate atypical lipomatous tumors, as well as differentiate between lipomas and higher-grade liposarcomas.

Atypical lipomatous tumors are predominantly isointense to fat on T1 and fat-suppressed T2-weighted sequences, with thickened septae coursing through the mass that enhance on post-contrast sequences (Figure 1 A, B and C). They can be distinguished from lipomas by the presence of so-called stranding, namely linear signal abnormalities with irregular margins within the fatty mass that suggest fibrous tissue or non-lipomatous elements. Other clues include thickened septae (greater than 2 mm) which enhance on post-contrast imaging sequences, larger size (often greater than 13 cm), and intramuscular location. The presence of solid, non-lipomatous areas within the tumor suggests the presence of dedifferentiated liposarcoma with the pre-existing ALT. However, intramuscular lipomas can have muscle fibers coursing through them that look like septae, and atypical lipomatous tumors can lack obvious stranding.

Figure 1: (A) Coronal T1-weighted sequence demonstrating a large lipomatous mass within the posterior compartment of the thigh. Notice the internal septations. (B) Coronal short tau inversion recovery (STIR) sequence demonstrating isointensity of the mass to fat. (C) Coronal post-contrast sequence demonstrating enhancement along the septations. Notice the absence of solid-enhancing areas within the mass to suggest dedifferentiation.

Atypical lipomatous tumors and well-differentiated liposarcomas show fairly uniform fat density on CT scanning along with the presence of various amounts of fibrous stranding. If there is concern for dedifferentiation, positron emission tomography (PET) scans can be useful for detecting areas of heightened metabolic activity.

If an atypical lipomatous tumor has undergone malignant transformation to a liposarcoma, MRI will demonstrate an area of T1-hypointense and T2-fat-suppressed hyperintense nodularity within the fatty tumor. These regions also enhance on post-contrast sequences, reflecting the cellularity of these regions.

Pathology

Grossly, atypical lipomatous tumors and well-differentiated liposarcomas are soft yellow masses with whitish, fibrous stromal bands and multiple lobules. There may be well-circumscribed, encapsulated areas as well as more infiltrative areas lacking a capsule (Figure 2).

Figure 2: Excised atypical lipomatous tumor from the thigh measuring nearly 30 cm in length.

Microscopically, atypical lipomatous tumor and well-differentiated liposarcoma are characterized by mature adipocytes with variable numbers of atypical lipomatous cells, which are characterized by a distinct cytologic appearance with enlarged and hyperchromatic nuclei (Figure 3). The atypical lipomatous cells may be arranged in sheets or nodules within the fatty background, and they can be interspersed with fibrous septa or areas of increased vascularity.

Figure 3: H&E stain of atypical lipomatous tumor. Notice the fibrous septae between areas of normal-appearing adipocytes, as well as the occasional atypical-appearing cell within these septae. (Image courtesy Drs. Amir Qorbani and Andrew Horvai)

Consistent with its low-grade nature, mitotic activity is usually low and necrosis is uncommon. Immunohistochemical analysis can be helpful in distinguishing atypical lipomatous tumors and well-differentiated liposarcomas from other adipocytic neoplasms and for confirming the diagnosis. The typical immunohistochemical profile of atypical lipomatous tumors and well-differentiated liposarcomas includes positivity for MDM2 and CDK4 markers. MDM2 is a negative regulator of the p53 tumor suppressor gene and plays a role in the regulation of cell growth and apoptosis. CDK4 is a cyclin-dependent kinase that regulates the cell cycle by phosphorylating and inactivating the retinoblastoma protein. The amplification of the MDM2 and CDK4 genes on chromosome 12q13-15 leads to overexpression of these proteins, which promotes cell growth and inhibits apoptosis. This overexpression of MDM2 and CDK4 is a characteristic feature of atypical lipomatous tumors and well-differentiated liposarcomas and can be used to confirm the diagnosis. Other markers that may be positive include S100, desmin, and smooth muscle actin. However, these markers are less specific and may be positive in other types of soft tissue tumors as well.

Atypical lipomatous tumor and well-differentiated liposarcoma can each be further subdivided into “lipoma-like” or “sclerosing” categories based on the degree of fibrosis present. The lipoma-like subtype is characterized by a well-circumscribed mass with a lobular appearance, demonstrating minimal fibrous stroma. As such, the amount of fibrous tissue in this subtype is minimal. On the other hand, the sclerosing subtype is characterized by a dense fibrous stroma with a relative paucity of adipose tissue. This subtype may have a higher risk of local recurrence and a worse prognosis than the lipoma-like subtype.

Differential Diagnosis

The differential diagnosis for atypical lipomatous tumor and well-differentiated liposarcoma includes other types of lipomatous tumors, as well as non-lipomatous tumors that can mimic their appearance. Some of the possible differential diagnoses include benign lipoma, dedifferentiated liposarcoma arising from a pre-existing liposarcoma, pleomorphic liposarcoma arising de novo, spindle cell lipoma, myxoid liposarcoma, and low-grade fibromyxoid sarcoma. Of note, aggressive liposarcomas will have areas of high T2 signal within the mass. MDM2 is useful for distinguishing atypical lipomatous tumors from plain benign lipomas, which are negative for this amplification.

Disease Course: Treatment and Prognosis

The clinical prognosis of an atypical lipomatous tumor and a well-differentiated liposarcoma depends primarily on the anatomic location. As noted, retroperitoneal lesions have a particularly worse course, primarily because of late detection and their invasion into the complex adjacent anatomy. In general, atypical lipomatous tumors can be locally aggressive and invade surrounding tissues and structures, but they tend to grow slowly and do not spread to distant sites in the absence of de-differentiation. Well-differentiated liposarcomas can metastasize, but have a relatively low risk of doing so, estimated to be around 5 to 10%. Metastasis occurs only after dedifferentiation. The most common sites of metastasis are the lungs and soft tissues, but metastases to bone and other sites have also been reported.

Both tumors are at risk for local recurrence and malignant transformation to a dedifferentiated liposarcoma. Dedifferentiation often occurs after a local recurrence.

Several studies have reported a 100% local recurrence-free survival at 5- and 10-years following wide resection of a lipoma-like atypical lipomatous tumor and well-differentiated liposarcoma of the extremity or chest wall. In practice, however, many tumors are treated with marginal excision, not wide resection, because the latter would be associated with excessive morbidity. Rates of local recurrence following marginal excision vary depending on the subtype, with an average rate of about 15% across all subtypes. For example, the sclerosing atypical lipomatous tumor tends to have a higher rate of local recurrence than lipoma-like atypical lipomatous tumor (~50% versus ~15%). The risk of dedifferentiation in extremity atypical lipomatous tumors is 10 to 15%. The choice of surgical procedure must be made in a process of shared decision-making, balancing the risks of local recurrence and surgical morbidity.

Retroperitoneal well-differentiated liposarcoma are associated with higher rates of both local recurrence and dedifferentiation (75% and 20%, respectively) in comparison to tumors located in the extremity or chest wall. Despite having very low metastatic potential, well-differentiated liposarcoma in the retroperitoneum carries a 15-20% risk of death at 5-years due to the morbidity of surgical excision, recurrence, local invasion, and obstruction.

Key Test Topics

Unlike lipomas, atypical lipomatous tumors show MDM2 amplification on fluorescence in situ hybridization (“FISH”) as well as immune-positive nuclear staining for MDM2 and/or CDK4.
Compared to lipomas, atypical lipomatous tumors on MRI have thickened septae (greater than 2 mm), enhancing septae on post-contrast sequences, larger size, and an intramuscular location.
The preferred surgical treatment is marginal resection.
Extremity atypical lipomatous tumors carry a high risk of local recurrence (up to 20% at 10 years).
Retroperitoneal well-differentiated liposarcomas carry an even higher risk of local recurrence (up to 75%), a moderate risk of dedifferentiation (around 20%), and a 15-20% risk of death due to disease at 5 years.